Brain and Gene Expression Responses to Exercise in Chronic Back Pain (CLBPE)

Frontostriatal Connectivity and Gene Expression in Exercise-induced Relief of Back Pain

This study is registered retrospectively for transparency. This mechanistic randomized controlled trial examined whether a 14-week supervised physical exercise training program reduces chronic low back pain (CLBP) by modulating frontostriatal brain connectivity and immune-related gene expression. Fifty-seven adults with CLBP were randomized to exercise training or wait-list control. Participants underwent pre- and post-intervention MRI, questionnaires, and blood sampling. The study tested whether reductions in nucleus accumbens-medial prefrontal cortex connectivity and changes in inflammatory gene expression mediated exercise-induced pain relief.

Study Overview

• Status: Completed
• Conditions: Chronic Low Back Pain (CLBP)
• Intervention / Treatment: Behavioral: Supervised physical exercise training

Detailed Description

Chronic low back pain (CLBP) is associated with altered functional connectivity between the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), as well as systemic low-grade inflammation.

This mechanistic randomized controlled trial evaluated the effects of a 14-week supervised physical exercise (PE) training program on pain intensity, functional disability, brain connectivity, and peripheral gene expression in individuals with CLBP.

Participants were randomized to either:

• Supervised exercise training (3 sessions per week, 60 minutes per session, 14 weeks), or
• Wait-list control.

Exercise sessions combined aerobic and resistance training. Exercise intensity was individually calibrated based on VO2max and 1 repetition maximum (1RM) assessments.

Assessments conducted pre- and post-intervention included:

• Resting-state functional MRI
• Diffusion-weighted imaging
• Self-reported pain and disability questionnaires
• Cardiorespiratory and functional testing
• Blood sampling for BDNF and RNA sequencing

The primary mechanistic hypothesis tested whether changes in NAc-mPFC connectivity and immune-related gene expression mediated exercise-induced reductions in chronic pain. Therefore, primary outcomes focused on indices of target engagement (including immune gene expression and brain connectivity) rather than clinical efficacy alone.

Note: This study was not registered prior to participant enrolment. The project was investigator-initiated and conceived as a mechanistic investigation prior to widespread mandatory registration requirements. Study recruitment and progress were also substantially influenced by the COVID-19 pandemic and associated lockdowns.

The clinical efficacy of PE for CLBP is already well established. Consequently, the primary aim of the present study was to examine the biological mechanisms through which PE may influence pain. Registration is therefore being completed retrospectively to ensure transparency.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3W 1W4
      • Centre de Recherche de l'Institut Universitaire de Geriatrie de Montreal

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years
• Chronic low back pain ≥ 3 months
• Pain present at least half the days over the past 6 months
• Average pain intensity ≥ 3/10 during week prior to enrollment

Exclusion Criteria:

• Diabetes
• Neurological disorder
• Psychiatric disorder
• Significant cardiorespiratory disease
• Under 18 years of age

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active intervention; Physical exercise training	Behavioral: Supervised physical exercise training; 60-minute sessions 3 times weekly Aerobic + resistance training Individually calibrated intensity (VO2max, 1RM) Total duration: 14 weeks
No Intervention: Waitlist control; Participants underwent all assessments but did not receive exercise training during the 14-week study period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chronic Low Back Pain Intensity	Self-reported average low back pain intensity measured using an 11-point Numerical Rating Scale (NRS; 0-10), where 0 = "no pain" and 10 = "worst imaginable pain."	Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 14)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oswestry Low Back Pain Disability Index (ODI)	Pain-related disability measured using the Oswestry Low Back Pain Disability Questionnaire (10 items). Each item is scored from 0-5, yielding a total score ranging from 0-50, with higher scores indicating greater disability.	Assessed at Baseline (Week 0) and Post-intervention (Week 14)
Nucleus Accumbens-Medial Prefrontal Cortex Functional Connectivity	Functional connectivity assessed using resting-state functional magnetic resonance imaging (rsfMRI). Seed-to-voxel analyses were performed using anatomically defined bilateral nucleus accumbens and medial prefrontal cortex regions.	MRI acquired at Baseline (Week 0) and Post-intervention (Week 14)
Whole-Brain Intrinsic Connectivity	Intrinsic connectivity analysis (voxel-wise network centrality; root mean square of all connections) performed using resting-state fMRI.	MRI acquired at Baseline (Week 0) and Post-intervention (Week 14)
Fractional Anisotropy of NAc-mPFC White Matter Tract	Fractional Anisotropy (FA) measured using diffusion-weighted imaging (DWI) probabilistic tractography along the white matter tract connecting the nucleus accumbens and medial prefrontal cortex.	MRI acquired at Baseline (Week 0) and Post-intervention (Week 14)
Peripheral Blood Gene Expression (RNA Sequencing)	Gene expression levels assessed in peripheral blood immune cells using RNA sequencing (DESeq2 analysis). Transcriptomic analyses evaluated differential gene expression and pathway enrichment.	Blood samples collected prior to Session 7 (first calibrated-intensity session, Week 3) and prior to Session 42 (final session, Week 14)
Plasma Brain-Derived Neurotrophic Factor (BDNF)	Plasma BDNF concentrations measured using Luminex multiplex assay (Human ProcartaPlex). The purpose of this outcome is to evaluate both acute and longer-term neurotrophic responses to exercise training. Acute changes were measured before and after high-intensity training sessions; long-term changes were assessed by comparing baseline levels across sessions.	Collected immediately before and after Session 7 (Week 3) and immediately before and after Session 42 (Week 14)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Submaximal Aerobic Power (subMAP85%)	Submaximal aerobic power assessed during a graded exercise test at 85% of estimated maximal capacity. Measured in watts (W).	Assessed at Baseline (Week 0) and Post-intervention (Week 14)
Six-Minute Walk Distance	Functional exercise capacity measured using the 6-Minute Walk Test (6MWT). Distance walked in meters during 6 minutes was recorded.	Assessed at Baseline (Week 0) and Post-intervention (Week 14)

Collaborators and Investigators

• Sponsor: McGill University
• Collaborators: Canadian Institutes of Health Research (CIHR)

Publications and helpful links

General Publications

• Baliki MN, Petre B, Torbey S, Herrmann KM, Huang L, Schnitzer TJ, Fields HL, Apkarian AV. Corticostriatal functional connectivity predicts transition to chronic back pain. Nat Neurosci. 2012 Jul 1;15(8):1117-9. doi: 10.1038/nn.3153.
• Hird EJ,Slanina-Davies A,Lewis G,Hamer M,Roiser JP
• Jiang R,Geha P,Rosenblatt M,Wang Y,Fu Z,Foster M,Dai W,Calhoun VD,Sui J,Spann MN,Scheinost D
• Geneen LJ,Moore RA,Clarke C,Martin D,Colvin LA,Smith BH
• Parisien M,Lima LV,Dagostino C,El-Hachem N,Drury GL,Grant AV,Huising J,Verma V,Meloto CB,Silva JR,Dutra GGS,Markova T,Dang H,Tessier PA,Slade GD,Nackley AG,Ghasemlou N,Mogil JS,Allegri M,Diatchenko L
• Lesnak JB,Berardi G,Sluka KA
• Schwartz N,Temkin P,Jurado S,Lim BK,Heifets BD,Polepalli JS,Malenka RC

Helpful Links

• Study pre-print

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2017
• Primary Completion (Actual): December 14, 2021
• Study Completion (Actual): December 14, 2021

Study Registration Dates

• First Submitted: March 14, 2026
• First Submitted That Met QC Criteria: March 14, 2026
• First Posted (Actual): March 18, 2026

Study Record Updates

• Last Update Posted (Actual): March 18, 2026
• Last Update Submitted That Met QC Criteria: March 14, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: chronic pain; back pain; inflammation; physical exercise; brain connectivity
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Back Pain; Chronic Pain; Inflammation; Motor Activity
• Other Study ID Numbers: CLBPE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No